Leprosy, caused by the intracellular pathogen Mycobacterium leprae, results in irreversible nerve damage and atrophy of peripheral tissues. The disease exhibits a range of clinical presentations from tuberculoid (T-lep) or paucibacillary disease to lepromatous (L-lep) or multibacillary leprosy that correlate with well-defined Th1 and Th2 immunologic states. Patients may develop sudden and acute changes in their immune status (reactional states). Most studies on M. leprae have been carried out using cells from leprosy patients, in which the immunological milieu has been altered by the infection. Thus, while the different clinical forms of the disease and their immunology have been well defined, the mechanisms underlying the establishment of divergent clinical presentations in leprosy remain unclear. To capture the critical early events in M. leprae infection that may contribute to outcome, we use nave cells from healthy blood donors. Our studies comparing the immune responses in monocytes exposed to Mycobacterium bovis bacillus Calmette-Guerin (BCG) versus M. leprae suggest that the response to BCG favors classical monocyte activation (M1), while the response to M. leprae is directed toward the alternative monocyte activation (M2) state. Exposure of nave cells to M. leprae or its cell wall phenolic glycolipid PGL-1 induces a very weak pro-inflammatory Th1 type cytokine response and the robust production of down-regulatory immune mediators which may interfere with the establishment of a Th1 type protective immune response. The focus of this proposal is to characterize the pathway-related molecular events underlying the monocyte response to M. leprae. Using monocytes from healthy donors, we will examine the early intracellular events following monocyte exposure to M. leprae to better understand how the bacilli direct monocytes away from the protective Th1 response (Aim 1). In addition we will examine whether prior M1 monocyte activation by IFN-? or BCG is reversed by subsequent exposure to M. leprae, by using nave monocytes pre-directed toward classical M1 activation by IFN-? in vitro, or monocytes from BCG-vaccinated and unvaccinated babies. The results of our proposed studies will facilitate the development of improved pharmacologic and/or vaccine strategies that can contribute to leprosy control.